Diabetes is a modern epidemic affecting an increasingly large number of populations from industrial countries to the developing world. The cost of managing diabetes in the United States alone is about $174 billion, $116 billion of which are directed towards medical care.
The hallmark symptom of diabetes mellitus is hyperglycemia, i.e. high levels of blood glucose (also known as blood sugar). Such conditions are primarily the result of insufficient insulin production (Type I diabetes) or from defects in response to insulin action (Type II diabetes). A chronic diabetic condition causes serious complications or co-morbidities, such as heart disease, stroke, impaired renal function, or nephropathy, high blood pressure, both central and peripheral nerve damage or neuropathy, cataracts and/or blindness and amputations.
According to the National Diabetes Information Clearinghouse (NDIC) report (a service provided by National Institute of Diabetes and Digestive and Kidney Diseases, NIDDK, NIH), in the United States, in 2007 there were 23.6 million (approximately 7.8 percent of the population) diabetic patients along with 1.6 million new cases of diabetes diagnosed in the same year. About half (12.1 million) of the diabetic population is age 60 or older. Moreover, an estimated 57 million American adults exhibit pre-diabetic conditions (e.g. persistent hyperglycemic conditions) in 2007, a warning sign of potential outbreak.
The etiology of diabetes is still under investigation. The primary focus of diabetic management is the reduction of blood glucose levels. Few therapeutic initiatives with regard to diabetic management started with a neurological approach. Mediating and attenuating diabetic neurological symptoms are often afterthoughts.
Diabetic conditions are often linked with altered central and sympathetic nervous systems. Most chronic diabetic patients eventually develop neuropathy of different clinical manifestations. According to a statement made by the American Diabetes Association, the most common among the neuropathies are chronic sensorimotor distal symmetric polyneuropathy (DPN) and the autonomic neuropathies. Up to 50% of DPN may be asymptomatic but the patient is at risk of insensate injury to their feet and >80% of amputations follow a foot ulcer or injury. Additionally, such neuropathy also includes autonomic manifestations of every system in the body, which causes substantial morbidity and increased mortality, particularly when cardiovascular autonomic neuropathy (CAN) is present. Glucose and/or insulin are not known to directly mediate sensory or nociceptive perceptions such as hypoalgesia or hyperalgesia (different neuropathic manifestations), nor are they known to be linked with cardiovascular autonomic regulations. Literature reports indicate that strict glycemic control may mediate neuropathies, but not eliminate the symptoms entirely. These indications point to other neurological mediators that 1) contribute to the regulation of glucose/energy homeostasis and 2) are dis-regulated under pre-diabetic or diabetic conditions (genetic and/or environmental factors).
Epidemiological studies have linked child-hood obesity and diabetes with neurological dysfunctions like attention deficit hyperactive disorder (ADHD). These studies suggest that dopaminergic transmission that evolved to increase cognition is also coupled with attention and energy management (Campbell and Eisenberg, 2007). One of the working hypotheses regarding ADHD etiology is that patients have handicapped energetic management between neuronal and glial cells (Russell, et al 2006). Besides ADHD, there is a substantial body of clinical evidence and research reports linking anxiety, stress and depression with diabetes. These mechanisms are still to be explored and understood. Nevertheless, the response of neuroendocrine, hypothalamic-pituitary-adrenal axis and sympathetic nervous system, to stressors may be key contributing factors to the underlying etiology. Based on these studies, a panel of experts has suggested that activation of the dopaminergic circuitry may be a viable and effective clinical management paradigm (Blum et al, 2008).
Diabetes alters the central and sympathetic nervous systems that may lead to behavior manifestations. Stress and depression, central nervous system conditions, may cause metabolic changes leading to diabetes. These disease symptoms may share common roots. To further support the role of neuronendocrine system in diabetes, especially with regards to the role of dopaminergic function, there is a substantial body of supporting evidence from animal studies When treated neonatally with monosodium glutamate, Wistar rats develop symptoms of Type II diabetes, i.e. hyperglycemia, glucose intolerance, beta-cell morphological changes, and sensory and autonomic nerve changes including the development of a hypoalgesic state. Concomitantly, there are noted changes in catecholamine synthesis in different peripheral tissues and sympathetic nerves (Morrison et al, 2007).
In one animal model of Type I diabetes (Sprague-Dawley rats treated with Streptozotocin), a brief episode of the chemically induced diabetes brought changes in dopaminergic neurotransmission by reducing levels of dopamine in a tissue specific manner. Notably, in the peripheral (sympathetic) nervous system, dopamine content remains unperturbed at adrenal glands, blood serum and cardiac ventricles; yet there is a 14 to 15 fold reduction of dopamine in the stellate ganglion (physiologically, the human stellate ganglion, or cervicothoracic ganglion, may be blocked for different medical conditions; reduction of catecholamine may be an indication of the reduction of catecholamine neurotransmission in the sympathetic nerves system leading to conditions such as DPN). In the central nervous system, dopamine levels remain unchanged at medulla and pons; however, there is a 4-fold reduction in the midbrain and a 5-fold reduction in the striatum (a underlying biochemical mechanism of neurological manifestations and symptoms, such as ADD, depression, anxiety and Parkinson's disease). Changes in other catecholamines, e.g. norepinephrine and epinephrine, are noted but less significant (Gallego et al, 2003). In another study, besides similar observations in altering catecholamine levels in different brain regions, short term diabetes also altered the expression levels of signal transduction proteins such as CaMKII, PKC-alpha, and p38-MAPK kinases, indicating the impact of diabetes at the neuronal level (Ramakrishnan et al, 2005) and changes in cellular signal transductions.
Human epidemiological studies have shown that when humans are on a limited caloric diet, there are fewer incidences of diabetes, as well as cancer, obesity, anxiety, depression and many other disease states and conditions. When the BL/6 is on a healthy and constant caloric restriction diet (recapitulating human condition), the animal subjects show less anxiety and less depressive behavior; that is the caloric-restricted (CR) subjects spend more time in the center of the open field study; more time in the open arm of the elevated plus maze study, and less time immobilized in the forced swim test (as compared with binge fed and normal control models). Dopaminergic and alpha-adrenergic signal transduction are amongst the top up-regulated genes (potentially indicating the underlying mechanism between ADHD and diabetes) in these CR subjects. And the western blot analysis indicated a specific activation of dopaminergic activities (e.g. up-regulation of cAMP-regulated phosphoprotein, a protein specifically associated with dopaminergic neurotransmissions).
From the above discussions, it may be concluded that 1) the diabetic condition appears to negatively impact the catecholaminergic, especially dopaminergic systems leading to conditions of neuropathology; and/or 2) neuropathological conditions may negatively impact the “insulinergic” system, thus supporting the diabetic condition. There is increasing evidence in the literature indicating the importance of insulin in neurological functions, including age-related neurodegenerative conditions such as Alzheimer's disease.
There is currently no cure for either Type I or Type II diabetes. Life style changes, e.g. changing diet and increasing exercise, may mediate aspects of disease-related conditions, but such changes and alternatives are often neither feasible nor effectively adopted, especially in aging populations. Pharmacological management is the primary means to control the development of diabetic complications.
For Type I diabetes, the management has been with insulin. Pharmacological intervention of Type II diabetes has been attempted with blood glucose control using medications such as Metformin (glucophage) or Glibenclamide (glyburide). Metformin inhibits the release of glucose from liver glycogen; Glibenclamide (and other sulfonylureas), inhibits pancreatic beta-cell potassium channels, and thus stimulates insulin secretion. Although these drugs are mostly safe, they cannot be used in patients with compromised hepatic functions. There are other drugs that mediate the diabetic condition by alternative biochemical mechanisms, e.g. stimulating insulin secretion (e.g. repaglinide), inhibiting glucose metabolism (e.g. glucosidase inhibitor, acarbose), mediating gastric emptying (e.g. pramlintide), etc. The most recent diabetic medications are agonists of glucagon-like peptide-1 of the incretin hormone receptor (GLP-1 agonist) and dipeptidyl-peptidase-4 inhibitors (e.g. sitagliptin). A common complication of most of these drugs is hypoglycemia, a condition often resulting in seizures, unconsciousness and occasionally permanent brain damage or death. Ideally, a pharmacological agent capable of maintaining glucose homeostasis at a healthy level without such complications would improve the current diabetes treatment paradigm.
The human clinical evidence, human epidemiological and animal model studies referred to above support the concept that activation of the dopaminergic circuitry may be a viable and effective clinical management approach for both Type I and Type II diabetes.